文章基本信息

标题：Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways
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作者：Xiaofeng Zheng ; Sarah Linke ; José M. Dias 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2008
卷号：105
期号：9
页码：3368-3373
DOI：10.1073/pnas.0711591105
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Cells adapt to hypoxia by a cellular response, where hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) becomes stabilized and directly activates transcription of downstream genes. In addition to this "canonical" response, certain aspects of the pathway require integration with Notch signaling, i.e., HIF-1{alpha} can interact with the Notch intracellular domain (ICD) to augment the Notch downstream response. In this work, we demonstrate an additional level of complexity in this cross-talk: factor-inhibiting HIF-1 (FIH-1) regulates not only HIF activity, but also the Notch signaling output and, in addition, plays a role in how Notch signaling modulates the hypoxic response. We show that FIH-1 hydroxylates Notch ICD at two residues (N1945 and N2012) that are critical for the function of Notch ICD as a transactivator within cells and during neurogenesis and myogenesis in vivo. FIH-1 negatively regulates Notch activity and accelerates myogenic differentiation. In its modulation of the hypoxic response, Notch ICD enhances recruitment of HIF-1{alpha} to its target promoters and derepresses HIF-1{alpha} function. Addition of FIH-1, which has a higher affinity for Notch ICD than for HIF-1{alpha
关键词：gene regulation ; hydroxylation ; signal transduction